title: Polymorphisms of renin--angiotensin system genes as a risk factor for high-altitude pulmonary oedema.
abstract: The genes of the renin--angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p < 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene--gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.
authors.affiliation: Institute of Genomics and Integrative Biology, India.
authors.forename: Tsering
authors.initials: T
authors.lastname: Stobdan
authors.forename: Zahara
authors.initials: Z
authors.lastname: Ali
authors.forename: Amjad Pervez
authors.initials: AP
authors.lastname: Khan
authors.forename: Azim
authors.initials: A
authors.lastname: Nejatizadeh
authors.forename: Rekhbala
authors.initials: R
authors.lastname: Ram
authors.forename: Tashi
authors.initials: T
authors.lastname: Thinlas
authors.forename: Ghulam
authors.initials: G
authors.lastname: Mohammad
authors.forename: Tsering
authors.initials: T
authors.lastname: Norboo
authors.forename: Gidugu
authors.initials: G
authors.lastname: Himashree
authors.forename: Ma
authors.initials: M
authors.lastname: Qadar Pasha
mesh_terms: D000328:Adult; D000483:Alleles; D000531:Altitude; D000532:Altitude Sickness / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D058011:Multifactor Dimensionality Reduction; D011110:Polymorphism, Genetic; D012084:Renin-Angiotensin System / Q000235:genetics*; D012307:Risk Factors